GOLD 2017 Report: Chiesi Farmaceutici highlights relevant gaps

Chiesi Farmaceutici welcomes the recently published GOLD report but identifies three key elements in the treatment recommendations, which deserve thorough evaluation and further revision:

Limited evidence base

Misalignment with approved product indications

Conflict with recent position of the European Medicine Agency

Parma, December 6, 2016 – Chiesi Farmaceutici welcomes the recent update of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report made public on November 16th, 2016 (1). The GOLD report has represented an important strategy document for many in the clinical and R&D community, and is compiled by a highly respected panel of international experts in the field.

Such a revision of the document is a positive step forward since the last update in 2011, when the new A-B-C-D categorisation of patients was introduced, based on the contemporary assessment of lung function impairment, severity of symptoms and risk of future exacerbations. The inclusion of these three domains of clinical assessment into a bi-dimensional scheme generated some challenges in patient categorisation (e.g. category C and D had subsequently to be divided into three different sub-categories depending on the presence of either one or both risk factors, i.e. FEV1 stage and risk of exacerbations). However, although this exemplifies some of the constructive elements to the document, there are a number of key elements which require closer attention and clarification.

“The evidence base of the new version of the GOLD report is limited in certain key areas, since, as clearly written in the body text, the basis for treatment recommendations is only partially from evidence coming from randomised clinical trials” said Professor Stefano Petruzzelli, Chief Medical Officer and Head of Global Clinical Development for Chiesi Farmaceutici. “Although inflammation has been removed from the disease definition, a substantial part of the pathophysiology section is still focusing on the inflammatory pattern in COPD with greater attention to the impact of the inflammatory reaction at the level of small airways, as compared to the previous version. However this underlying cardinal feature of the disease is then apparently missed or given lower priority in the treatment recommendations,” Professor Petruzzelli continued.

More importantly, the clear statement that the goal of treatment of stable COPD is to reduce symptoms and risk of exacerbations is then substantially missed when LABA/LAMA are recommended instead of LAMA (e.g. as first choice in category D patients), since there is no evidence that LABA/LAMA can significantly (i.e. to a clinically relevant extent) reduce the risk of exacerbations compared to LAMA (2-4).

A recent study reported that a specific LABA/LAMA (5) was superior to a specific ICS/LABA product in terms of exacerbations. However, this effect was not demonstrated in patients with a history of more than one exacerbation, and group C patients were not included in the study. Consequently, the recommendation to step up from LAMA to LABA/LAMA is at least questionable and not supported by evidence. Indeed, this is clearly stated in the GOLD report “There is a lack of direct evidence for therapeutic recommendations for patients in group C and D”.

Even more important, the new document pointing to LABA/LAMA as the first option in group D patients and as step up from LAMA in C patients is not in line with the approved indications of all LABA/LAMA currently available to healthcare professionals (6-9). The regulatory agency-approved indications for these products are essentially restricted to relieve symptoms, and notably do not include the use in patients with history of exacerbations. In short, the GOLD report therefore appears to be recommending off label and unapproved clinical use of these products in patients at high risk of exacerbations, notwithstanding the statement in the report that the GOLD Committee does not make recommendations for therapies that have not been approved by at least one major regulatory agency.

In addition, there is a repeated reference in the text to the well-known risk of pneumonia with the use of inhaled corticosteroids (ICS). A clear reference to the positive risk-benefit ratio with use of ICS in COPD (i.e. the marked reduction of exacerbations being significantly greater than the increase of pneumonia), as recently established by the European Pharmacovigilance Risk Assessment Committee (PRAC) (10) and endorsed by the CHMP and European Commission, would have represented a more balanced vision to support the treatment recommendations. Moreover, there is no mention to the fact that this increase risk does not translate into a greater risk of death (11).

In summary, Professor Petruzzelli concludes: “We consider that the new GOLD report is not fulfilling the goal of clarifying the therapeutic approach to COPD patients compared with previous recommendations based on a convincing level of evidence, and regrettably it adds practical complications in the use of the therapeutic armamentarium available to physicians to help patients lower symptom burden and reduce risk of life-threatening acute exacerbations of their disease”. He continued “The huge amount of data produced since the last 2011 GOLD report certainly deserves detailed evaluation and, in case of need, confirmatory studies might be required to ensure the strength of recommendations, which comes from a solid evidence base. This is where, in our opinion, the new GOLD 2017 report falls short.”

About Chiesi Farmaceutici

Headquartered in Parma, Italy Chiesi Farmaceutici is an international research-focused Healthcare group, with over 80 years of experience in the pharmaceutical industry. Chiesi researches, develops and markets innovative drugs in the respiratory therapeutics, specialist medicine and rare diseases areas. Its R&D centres in Parma (Italy), Paris (France), Cary (USA), Chippenham (UK) and the R&D team of the acquired Danish company Zymenex, integrate their efforts to advance Chiesi's pre-clinical, clinical and registration programs. Chiesi employs over 4,500 people, 560 of whom are solely dedicated to R&D activities. For more information, please visitwww.chiesi.com

About GOLD

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) program was launched in 1998 with the aim of producing recommendations for management of Chronic Obstructive Pulmonary Disease (COPD) on the basis of the best scientific information available. The first report was issued in 20001 and complete revisions have been published every five years (2006 and 2011). Updates of the 2011 report have been released yearly since 2013. The 2017 Report represents the 4th major revision based on the most recent information and a reassessment of prior recommendations for the diagnosis, assessment and treatment of COPD. The GOLD Report has been used worldwide as a “strategy document” for healthcare professionals to use a tool to implement effective management programs based on local healthcare systems.

About COPD

COPD is a respiratory disease characterized by a persistent bronchial obstruction, associated with an increased chronic inflammatory response of the airways to noxious particles or gas. The classic symptoms associated with COPD are dyspnoea, chronic cough and chronic productive sputum. In some cases, an acute worsening of the above-mentioned symptoms may occur, triggering an exacerbation. A double mechanism is at work in the bronchial obstruction in COPD patients: on one hand, an inflammation of the small airways together with the thickening of the airways walls and increased airflow resistance may occur. On the other, a progressive destruction of lung parenchyma (emphysema) associated with the loss of elastic retraction of the lung may take place. It is important to underline that both mechanisms may coexist, leading to a significant airflow reduction throughout the lungs.